The present invention relates to an apparatus for an integrated process of magnetic particles and a method of controlling the same. Particularly, the present invention relates to an apparatus for an integrated process of magnetic particles and a method of controlling the same, which can execute processes such as reaction, separation, fixing quantity, dispensation, clarification, concentration, agitation, suspension, dilution, and operations such as observation, extraction, recovery, isolation, and indications in regard to for example, immune substances such as antibodies or antigens, genetic substances (DNA, RNA, m-RNA and so on), bacillus, and other useful substances such as medicines, or target substances, for medical treatment, inspection, diagnosis, medical care, research, quantitative analysis, qualitative analysis and so on in all manner of fields such as medical science, agricultural science, engineering, scientific fields, pharmaceuticals, by using a fluid incorporating magnetic particles and capable of being processed in large numbers in a vessel such as a microplate.
Currently, there is a pipette device shown in FIG. 21. As shown in this view, the pipette device has a magnet driving device for controlling to drive a magnetic source M and a holding body V The magnetic source M having a magnet section and the holding body V having a holding section, are rotatably mounted in an up-down mechanism of the pipette device in such a manner that they can approach and go away from one another.
When the up-down mechanism O moves vertically, as shown in FIG. 21, the magnetic source M and the holding body V move in obedience to movement of rollers RA RB of the up-down mechanism O so that they close in a way that they hold a tip between them. As a result, the magnetic source M and the holding body V can simultaneously come in contact with the pipette tip T in a manner that they hold the pipette tip T, and the magnetic source M can surely approach to the tip T and separate from the tip T.
In order to execute a process for large numbers of substances such as combinatorial chemistry, DNA function analysis, or automatic measurement of immune substances, many pipette tips are necessary. Currently, a multiplex pipette device having many pipette tips arranged in a line is used, as shown in FIG. 22. In regard to the conventional pipette device capable of processing magnetic particles, not only pipette tips but also mechanisms (M1, M2, M3, M4, V1, V2, V3, V4) which are mounted per each pipette tip for applying and removing a magnetic field to and from the pipette tip respectively by driving a magnet, need to be multiply provided and linked.
Therefore, though such a multi-linking using tips arranged in a line is embodied, such an integration as applying al magnetic filed to many lines of nozzles simultaneously by using the device causes the problem that the apparatus is scaled up in size and processes cannot be executed in an integrated state.
Particularly, when a large number of samples are handled and the wells (plate holes of a microplate) of a vessel are for example, 96 wells or 384 wells or more, driving sections for applying and removing the magnetic field to and from the nozzles and magnetic particles, need be integrated in high density. However, since the driving section prevents integration, there is a problem that the process for magnetic substances cannot be integrated.
The present invention aims to resolve the aforementioned problems. A first object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, that can promptly and efficiently process all together in high, precision, with integration of the process of magnetic particles, by integrating nozzles and sections for driving sections for applying the magnetic fields to the nozzles.
A second object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, which integrates the process for the magnetic particles without using a magnet driving device having elements whose scale or action range is large, and which can execute the process of a large number of substances with a small scale and compact device.
A third object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, in which a plurality of elements are integrated, the structure of elements per unit of integration is simplified and the cost performance is high.
A fourth object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, which is suitable for a microplate having a plurality of wells, and which has such diversity and flexibility that it can be applied to various fields requiring processes for large numbers of substances such as combinatory chemistry, DNA function analysis, and automatic measurement of immune substances, and has diversity and flexibility.
A fifth object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, which can exclude human operations to the utmost and facilitates automatization, in a process for fluids.
A sixth object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, which can exclude mechanical movement to the utmost, can work at a low running cost, has a long life span, and is easily handled.
A seventh object of the invention is to provide an apparatus for an integrated process of magnetic particles and a method of controlling the same, which can complete whole steps within a confined space and can exclude influence between the space and the outer environment to the utmost, and which can reliably execute the process.
In order to resolve the above technical problems, a first aspect of the invention is an apparatus which comprises a drawing/discharging device for drawing and discharging a fluid, plural nozzles for passing the fluid therethrough while drawing and discharging, and a magnetic force device for applying and removing a magnetic field to and from the nozzles respectively with remaining stationary near each nozzle exterior.
The xe2x80x9cdrawing/discharging devicexe2x80x9d comprises for example, a plurality of separate cylindrical containers being bundled, or a block in which plural cylindrical containers are formed. Each container comprises for example, a drawing/discharging line, a plunger, an elastic body, bellows or a diaphragm, for drawing and discharging a fluid. xe2x80x9cFluidxe2x80x9d includes a liquid and a gas. It also includes a fluid incorporating or suspending solid substances such as magnetic particles or magnetic substances.
xe2x80x9cPlural nozzlesxe2x80x9d are preferably arranged in a plane-like state for convenience sake, in which for example, a matrix-like state, a circular state and a two-dimensional state are included, but the plane-like state is not restricted to these examples.
xe2x80x9cNozzlexe2x80x9d may be fixed to the drawing/discharging device, or may comprise a pipette tip that is detachably mounted to the drawing/discharging device directly or to a section fixed to the drawing/discharging device.
The pipette tip includes a disposable type and a cleaning and a recycling type. xe2x80x9cMagnetic force devicexe2x80x9d serves to make the magnetic substances or magnetic particles suspended or incorporated in a liquid adhere to inner walls of the nozzles. Thus, a process for magnetic particles such as transferring, agitation, cleaning, separation, resuspension and so on can be executed. xe2x80x9cMagnetic force devicexe2x80x9d is one that can simultaneously apply and remove a magnetic field to and from the nozzles respectively, in a manner that the neighborhood of the outer side of the nozzles remains stationary. The structure does not require a complicated mechanism near the outer side of the nozzles or a space for movement. Therefore, a plurality of nozzles can be densely integrated, instead. Hence, the process for the magnetic particles can be integrated, the apparatus can be scaled down, the space can be reduced, and the process can be efficiently executed. Furthermore, since large numbers of small quantity objects can have conditions being equal and uniform in time and space, the process for each small quantity object can be executed in high precision. Since a large number of small quantity objects can be simultaneously processed, the process can be sped up and efficiency of the process can increase.
Here, since neighborhood of xe2x80x9ceach nozzle exteriorxe2x80x9d remains stationary, the case where a moving mechanism for applying and removing the magnetic field, is mounted at a part outside of the neighborhood of the nozzle exterior is not excluded. Furthermore, the case where the magnetic force device moves not for the purpose of applying and removing the magnetic field, but for transportation of the entire apparatus, is not excluded.
The magnetic force device is constructed, for instance, so that a part of each nozzle or nozzle outer member is made of a magnetic material such as a para-magnetic material or a super para-magnetic material etc. which is magnetically connected to an electromagnet having a switch, or a magnetic source such as permanent magnet or electromagnet capable of detaching therefrom.
xe2x80x9cMagnetic particles or magnetic substancesxe2x80x9d are processed so as to be able to combine with related substances such as target substances. The magnetic particles have a size of for example, about 0.1-100 xcexcm, and combine with the related substances by holding the related substances in a porous material having a plurality of recesses in the magnetic particles, by adsorbing the related substances, or by reacting the related substances with substances coated or held in the magnetic particles. For example, the magnetic particles are made of a super para-magnetic substance. Furthermore, the magnetic force device may be fixed to the drawing/discharging device, or may be detachably mounted.
A second aspect of the invention is an apparatus for an integrated process of magnetic particles according to the first aspect of the invention, wherein the magnetic force device can apply and remove the magnetic force to and from the nozzles respectively by enabling magnetization and demagnetization in a nozzle outer member brought in contact with or being near the outer surface of the nozzle or at least a part of the nozzle, with remaining stationary near each nozzle exterior.
xe2x80x9cMagnetization and demagnetizationxe2x80x9d implies that the magnetic material is magnetized under influence of the magnetic field and demagnetized without influence of the magnetic field.
With the present invention, since the magnetic force device can be simplified in structure, the structure of the entire apparatus can be simplified and the cost of the products can be reduced. Particularly, in the case of xe2x80x9cenabling magnetization and demagnetization in at least part of the nozzlexe2x80x9d, since the necessary volume or the bottom area for magnetization and demagnetization is small, integration is improved much more.
A third aspect of the invention is an apparatus for an integrated process of magnetic particles according to the second aspect of the invention, wherein the magnetic force device comprises a magnetic member made of a magnetic material and provided with a plurality of through sections capable of taking insertion of nozzles, wherein the nozzle outer member is a wall of the through sections. With the present invention, a plurality of nozzles can be easily and densely integrated by a simple structure. Consequently, the cost of products can be reduced, and the apparatus can be made to be compact.
xe2x80x9cMagnetic memberxe2x80x9d is made of for example, para-magnetic materials or super para-magnetic materials.
A fourth aspect of the invention is an apparatus for an integrated process of magnetic particles according to the second or the third aspect of the invention, wherein the nozzle outer member or a part of the nozzle comprises divided parts that are divided in two, wherein the divided parts are apart from one another in a manner that the divided parts have mutually opposite magnetic polarities.
The distance between the divided parts is one which can give an appropriate magnetic force within the nozzle. The distance is determined by considering the strength of the magnetic field of the magnetic source, the kinds of magnetic materials, the size of the through section, each location of the through section, or the distance from the magnetic source, the size of the magnetic force device, and the magnetic force necessary for the processes etc. When the distance between the divided parts is the shortest in the magnetic force device, the maximum magnetic force can be generated there compared to the sections having a longer distance between the divided parts.
With the present invention, the divided parts are apart from each other so that the lines of magnetic force can leak out in the places where required, and an appropriate magnetic force can be efficiently applied to the nozzle, without wastage, by leakage of the lines of magnetic force.
A fifth aspect of the invention is an apparatus according to the fourth aspect of the invention, wherein the magnetic force device comprises a magnetic source having an electromagnet or a permanent magnet, two magnetic plates made of magnetic material and connecting with the electromagnet or capable of connecting with the permanent magnet and capable of being magnetized and demagnetized, and mounted in face-to-face relationship in a low and a high position, plural through sections penetrating the two magnetic plates and capable of taking insertion of the nozzles, a pair of projections mounted in each through section, projecting to the opposite surface of each magnetic plate and made of magnetic materials, wherein the pair of the projections correspond to the nozzle outer member, and each projection corresponds to the divided parts and are apart from one another in such a manner that they have mutually opposite polarities by magnetization.
When an electromagnet is used as the magnetic source, generation and extinguishment of magnetic fields are executed by conducting and cutting off the electric currents, respectively. When a permanent magnet is used as the magnetic source, the magnetization and demagnetization can be executed by mounting and dismounting or touching and detaching. Touching and detaching are executed by for example, rotating a permanent magnet about an axis of rotation and touching or approaching, or separating the pole thereof to or from the magnetic member respectively.
xe2x80x9cThe magnetization and demagnetizationxe2x80x9d can be executed at positions far from each nozzle, without providing a driving mechanism or a drive space for each nozzle, by mounting and dismounting the permanent magnet to and from magnetic plates magnetically connecting with the wall parts mounted near each nozzle and made of magnetic material, or by conducting and cutting off the electric current. It thus follows that a plurality of nozzles can be arranged in an integrated state.
With the present invention, since the magnetic field being generated between the projections can be stronger than that, generated between the magnetic plates, the strong magnetic field leaking out between the projections can be applied to the nozzles, by mounting the projections projecting toward the opposite surfaces of the magnetic plates at a predetermined interval. xe2x80x9cA predetermined intervalxe2x80x9d is the distance that does not affect magnetic fields irrelevant to the process and that allows the nozzle to penetrate the through section.
A sixth aspect of the invention is an apparatus according to the fifth aspect, wherein the through section comprises through holes penetrating through the magnetic plates and projecting vertically and capable of taking insertion therethrough by the nozzles, and each wall part of the mutually separated through holes has opposite polarity respectively.
With the present invention, the magnetic field can be efficiently applied to within the nozzle without waste.
A seventh aspect of the invention is an apparatus according to the fifth aspect, wherein the magnetic force device comprises one or more magnetic sources, the magnetic source comprises a coil and a magnetic element provided with the coil, and one end of the magnetic element is connected with one of the two magnetic plates and the other end thereof is connected with the other thereof.
With the invention, since each magnetic plate connects with only one end or the other end of the magnetic element serving as the magnetic source, the magnetic plates are not directly touched. Therefore, a stronger magnetic field can be generated between the divided parts whose distance is shorter than that between the magnetic plates.
An eighth aspect of the invention is an apparatus according to the seventh aspect, wherein the magnetic elements are mounted outside of the space which is formed by the magnetic plates.
With the invention, since the magnetic elements are mounted outside of the space sandwiched between the magnetic plates, the turn number of the coil is not restricted by the interval between the magnetic plates, and a strong magnetic force can be generated.
A ninth aspect of the invention is an apparatus according to the eight aspect, wherein the magnetic elements comprise a first part and a second part which are separately mounted, wherein one end of the first part connects with one of the two magnetic plates, the other end of the second part connects with the other magnetic plate, wherein the first part and the second part are overlapped and are wound by wire of a coil, or the other end of the first part and one part of the second part are connected with each end of the third part and wound by wire of the coil and made of magnetic material.
With the invention, the magnetic element and magnetic plate can be easily produced by separating the magnetic element into a few simply formed parts.
A tenth aspect of the invention is an apparatus according to the fourth aspect, wherein divided parts being apart from one another, are tapered toward a gap. With the invention, since the line of the magnetic field can be densely generated on the outer side of the nozzle near the gap, a strong magnetic field can be applied to the nozzle. The tapered form implies for example, a truncated cone.
An eleventh aspect of the invention, is an apparatus according to the fifth aspect, wherein the pair of projections project from the opening edge of the through section of one of the magnetic plates to the other magnetic plate in a direction of insertion of the nozzle opposite to one another, and each tip of the projections is apart from the opposite surface at a first interval, and the tips of the projections are apart from one another separated from the nozzle at a second interval shorter than the first interval, in such a manner that the tips have opposite polarities, respectively.
The reason that the second interval is formed so as to be shorter than the first interval is so that the lines of the magnetic force can densely pass between the projections which are apart at the second interval.
A twelfth aspect of the invention is an apparatus according to the third aspect, wherein each through section of the magnetic force device comprises a separate hole in which the nozzle is inserted in a way that the outer surface of the nozzle can come in contact with or approach to the nozzle outer member, and an insert-withdraw hole mounted adjacent to the separate hole and having an opening larger than that of the separate hole so that the nozzle can horizontally move to and from the separate hole and can be withdrawn and inserted at the insert-withdraw hole.
The present invention needs a moving mechanism which can horizontally move the nozzle between the separate hole and the insert-withdraw hole and can vertically move the nozzle at the insert-withdraw hole, relative to the magnetic force device, as a precondition. The reason why the insert-withdraw hole is provided in addition to the separate hole is as follows.
A liquid is necessarily stuck on the periphery of the lower part of the nozzle which touches with the liquid accommodated in the vessel. Since the nozzle outer member mounted in the separate hole approaches or touches the nozzle, the liquid stuck to the periphery of the lower part may stick to the nozzle outer member and stain the nozzle outer member in the case where the nozzle comprising a pipette tip is pulled up from the through section. Once that happens, the nozzle outer member is stained, the nozzle outer member stains newly inserted nozzles, and cross-contamination may occur. Therefore, the nozzle is inserted in or withdrawn out from the through section, through the insert-withdraw hole whose opening is larger than that of the separate hole, so that the nozzle does not touch other members.
A thirteenth aspect of the invention is an apparatus according to the twelfth aspect, wherein the nozzle comprises a small diameter section and a larger diameter section, the separate hole has an opening that only the small diameter section can be inserted in, and the insert-withdraw hole has an opening that the larger diameter section can be inserted in.
With the invention, in the case where the nozzle has a small diameter section and a larger diameter section, the insert-withdraw hole has an opening that can take insertion of the larger diameter section. Thus, the opening can take insertion of the larger diameter section. Consequently the insert-withdraw hole is not stained by the small diameter section which is mounted in the lower section and touches the liquid, and cross contamination can be prevented. Further, since even the larger diameter section can be withdrawn and inserted, the nozzle can be easily inserted and withdrawn.
A fourteenth aspect of the invention is an apparatus according to the first aspect, wherein the magnetic force device can apply and remove the magnetic force to and from the nozzle with remaining stationary near each nozzle exterior.
With the invention, a uniform strong magnetic field can be applied to each nozzle at point-blank range.
Besides, the coil of the magnetic force device may be made of a single wire. Therefore, since ports etc. need not be Mounted per coil, the structure of the circuits can be simplified. Furthermore, since the coil is not mounted on the nozzle, the nozzle can be disposed of.
A fifteenth aspect of the invention is an apparatus according to the first aspect, wherein the magnetic force device comprises an insulating device for preventing heat generated by magnetization or generation of a magnetic field, from being transmitted toward the nozzle. With the invention, detrimental influence of heat on the nozzles can be avoided. Conversely, in a special case the heat may be positively utilized for the process without the insulating device. The insulating device may be one included in the fifteenth aspect, one provided by a Peltier effect element, or one provided for insulation against the magnetic sources.
A sixteenth aspect of the invention is an apparatus according to the fifteenth aspect, comprising a ventilator for sending air to the magnetic force device or the neighborhood thereof. Thus, transmission of heat to the nozzle can be efficiently prevented.
A seventeenth aspect is an apparatus according to the second aspect, wherein the magnetic force device comprises plural magnetic sources, and plural segments defined so as to include the area spatially near each magnetic source, respectively. For example, belt-like magnetic segments having through sections capable of taking insertion of a column of nozzles selected from the nozzles arranged in a plane-like state, are arranged in the direction of the magnetic field and have the same number of rows as the nozzles.
Therefore, in the case of manufacturing such a magnetic force device that can process a fluid by using a vessel having a plurality of liquid containing parts, the magnetic force device can be manufactured by being divided and the production cost can be reduced. The magnetic field can be uniformly distributed and a strong magnetic field can be applied.
An eighteenth aspect of the invention is an apparatus according to the third aspect, wherein the magnetic force device comprises a magnetic source having a permanent magnet or an electromagnet, and a plank-like member made of magnetic material and magnetically connected to the electromagnet or capable of magnetically connecting to the permanent magnet, wherein the through sections are provided in the plank-like member and are capable of taking insertion of the nozzles. With the invention, a magnetic force device having a simple structure is provided. For instance, xe2x80x9cthe plank-like memberxe2x80x9d may be formed by piling up thin plates made of magnetic material in the direction of magnetic force. With the invention, since the lines of magnetic force can be generated in the direction of the surfaces of the thin plates, leakage of magnetization can be suppressed to the minimum, and a uniform magnetic field can be obtained. Further, the thin plates can be piled up in a stratified state so that the normal direction of the thin plates is vertical or horizontal.
A nineteenth aspect of the invention is an apparatus according to the eighteenth aspect, wherein the through holes of the magnetic force device comprise divided wall parts divided in the direction of the insertion of the nozzle in such a manner that divided wall parts are apart from one another and have opposite polarities by magnetization.
A twentieth aspect of the invention is an apparatus according to the nineteenth aspect, wherein the nozzles comprise a larger diameter section and a small diameter section, and the plank-like member of the magnetic force device comprises plural column-like members arranged apart from each other at intervals capable of taking insertion of the larger diameter section of the nozzle, and plural protrusions made of magnetic material that are projected oppositely from each column-like member, magnetized in a manner that has opposite polarity to each other and arranged apart from each other at intervals capable of taking insertion of the smaller diameter section of the nozzle, and are arranged along the column-like member at intervals capable of taking insertion of the larger diameter section of the nozzle, wherein opposite pointed ends of the protrusions correspond with the divided wall parts. With the invention, since each column-like member is apart from each other, the lines of magnetic force run through the narrow interval between the pointed ends of the opposite protrusions. Therefore, a strong magnetic force can be supplied to the nozzles.
A twenty first aspect of the invention is an apparatus according to the second aspect, wherein the magnetic force device comprises a plank-like member made of magnetic material, plural through holes capable of passing a fluid and mounted in the plank-like member, small diameter pipes communicating with the through holes and capable of being inserted into a vessel and mounted under the through holes, wherein the through holes and the small diameter pipes serve as the nozzles. With the invention, since the nozzle itself constitutes the magnetic force device, the number of the members can be reduced, the apparatus can be formed to be compact, and a strong magnetic field can be applied into the nozzles.
A twenty second aspect of the invention is an apparatus according to the first aspect, wherein the drawing/discharging device comprises a reservoir body comprising plural reservoirs for storing a drawn fluid and communicating with the nozzles, and an increasing/decreasing device for increasing and decreasing pressure within the reservoirs and the nozzles in a manner that draws or discharges the fluid. The xe2x80x9creservoirsxe2x80x9d can store a fluid. It follows that the reservoirs can store not only a liquid, but also a gas such as air. Thus, a process can be executed in a state that an air layer can be formed between the drawn or discharging liquid and the increasing/decreasing device or, a cleaning liquid. The shape of the reservoirs may be for example, hole-like with a bottom, with no bottom, with a lid, or with no lid, or pipe-like, or vessel-like. Further, the reservoirs may be integrated with the nozzles or be separate from the nozzle. Furthermore, the number of reservoirs need not be the same to that of the nozzles.
For example, plural nozzles may communicate with a single reservoir. In the case where the number of nozzles is the same to that of the reservoirs, each nozzle may communicate with each reservoir one to one. Further a part of plural nozzles may jointly communicate with a single reservoir, or plural reservoirs may jointly communicate with a single nozzle.
Furthermore, the reservoir body which is an assembly of reservoirs, may be not only a plank-like one provided with plural hole-like reservoirs, but may be one with plural pipe-like or vessel-like reservoirs, assembled in a bundle.
With the invention, plural reservoirs can be simply manufactured in an integrated state by for example, piercing plural pits in the plank.
Moreover, the pressure may be increased and decreased by raising and lowering a sliding body as described in the fifteenth aspect. Further, the reservoir may have an expandable bellow mounted in a part of the side thereof and an opening connecting to the nozzle in a lower side thereof. The increasing/decreasing device may be a pressing device which presses the reservoirs and release the pressing of the reservoirs.
Furthermore, the increasing/decreasing device may comprise an inserting body which is made of an elastic solid at least partially, which can be inserted into the reservoirs by deformation and cover the top of the reservoirs, and a pressing device for pressing the inserting body for compressing the inside of the reservoir and releasing pressing thereof. Further, the reservoir may have a diaphragm and an opening mounted in the lower side thereof for connecting with the nozzle, and the increasing/decreasing device may be a pressing device for pressing the diaphragm and releasing pressing thereof.
A twenty-third aspect of the invention is an apparatus according to the twenty-second aspect, wherein the increasing/decreasing device comprises a sliding body capable of moving vertically to and from the reservoir body, and sliding projections projecting downward from the sliding body and capable of sliding through the nozzle in such a manner that the pressure within the reservoirs or nozzles increases or decreases.
With the invention, the apparatus has a simple construction. A fluid can be easily drawn or discharged with the same conditions for time, capacity and timing etc., all together, by moving the sliding body having plural sliding projections, to and from the reservoir body vertically.
A twenty-fourth aspect of the invention is an apparatus according to the twenty-third aspect, wherein the sliding projections are formed to have a two-step structure comprising a larger diameter section capable of sliding through the reservoir formed to be pit-like, and a smaller diameter section capable of extending along the axes of the larger diameter section and sliding through the nozzle communicating with the reservoir.
With the invention, when a relatively large amount of fluid is handled, drawing or discharging is executed by moving the sliding projections vertically in a state with the tip of the small diameter section and the tip of the larger diameter section fixed and aligned. On the other hand, when a relatively minute amount of fluid is handled, first, the sliding projections are moved vertically in a state with the tips of the small diameter section and the larger diameter section fixed and aligned. When the tips of the sliding projections stick to the lower part of the reservoir, drawing or discharging is executed by sliding only the small diameter section through the nozzle, vertically.
Thus, minute amounts of fluid as well as a relatively large amount of fluid can be processed at high precision. Therefore, an apparatus with reliability and diversity can be provided.
With the invention, residual liquid or remnants such as magnetic substances or particles remaining in the nozzles can be surely and efficiently discharged. Therefore the process for a fluid can be reliably executed.
Further, since the nozzles can be recycled by completely cleaning the nozzle with a cleaning liquid, cost for the process can be reduced in comparison to the case of using disposable nozzles or reservoirs. Here, though the sliding projection is formed to be two-steps, if necessary, the sliding projection may be formed to be multi-steps.
A twenty-fifth aspect of the invention is an apparatus according to the twenty-second aspect, wherein the nozzles comprise a tip capable of being mounted to and dismounted from the drawing/discharging device.
With the invention, cross contamination can be surely avoided without cleaning the nozzle. Therefore, since drawing and discharging can be executed through an air layer formed within the reservoir, the process can be efficiently executed, without cleaning.
A twenty-sixth aspect of the invention is an apparatus according to the twenty-fifth aspect, comprising a pushing body having pushing pipes inserted from the upper side of the reservoirs into the reservoirs and capable of pushing the nozzles out of the reservoirs, wherein the nozzles are detachably mounted to the reservoirs while being inserted from the lower side of the reservoirs, and the increasing/decreasing device comprises a sliding body having plural sliding projections projecting downward, capable of sliding through the pushing pipe and capable of moving vertically to and from the reservoirs respectively, in a manner that the pressure within the reservoirs or nozzles can be increased or decreased.
With the invention, since the process can be executed in such a manner that drawing or discharging liquid is apart from the pushing body by an air layer, cross contamination can be surely prevented by exchanging only the nozzle. Furthermore, the nozzles are detachably mounted to the reservoirs, and the nozzles can be easily dismounted all together by moving the pushing body downward.
A twenty-seventh aspect is an apparatus according to the twenty-fifth aspect, wherein the nozzles are detachably mounted to the lower part of pit-like reservoirs and are inserted to a predetermined depth in the pit-like reservoirs, the sliding projections can slide to a depth of the installation depth of the nozzles in the reservoirs, and a projecting lip part is projected from the outer side of the nozzles exposed under the magnetic force device for mounting and dismounting, and a stroke-down plate provided with plural small hole parts with respective diameters larger than that of the nozzles and smaller than that of the lip parts is mounted between the magnetic force device and , the lip parts in a way that the hole parts take insertion of the nozzles and the nozzles can be detached by moving the stroke-down plate down.
With the invention, the nozzle can be easily detached by moving the stroke-down plate downwards. Further, the sliding, projections do not touch with the liquid, and cross contamination can be surely prevented while drawing and discharging the liquid etc. through the medium of the air layer within the reservoir.
A twenty-eighth aspect is an apparatus according to the twenty-third aspect, wherein an inner wall of the upper part of the reservoir is formed to be cylindrical, and that of the lower part of the reservoir is formed to be funnel-shaped and is connected with the nozzles. With the invention, since the lower part thereof is formed to be funnel-shaped and the tip of the sliding projections is formed so as to fit closely with the lower part of the reservoir, residual liquid can be surely avoided and a process can be reliably executed.
A twenty-ninth aspect of the invention is an apparatus according to the first aspect, wherein the magnetic force device is constructed to be able to relatively move to and from the drawing/discharging device or the nozzle. With the invention, since the magnetic force device is constructed as mentioned above, the magnetic force device can surely apply and remove the magnetic force. For example, after the magnetic force by the magnetic force device is removed, the process for discharging etc. is executed by moving the drawing/discharging device upwards and keeping the nozzle away from the magnetic force device so that the effect by residual magnetization can be reduced. Furthermore, in the case where the nozzle is detachably mounted to the drawing/discharging device, the nozzle can be easily detached.
A thirtieth aspect of the invention is an apparatus according to the twenty second aspect wherein a cleaning liquid can be poured into each reservoir from the top or side of the reservoir body.
The invention is embodied, for example, by connecting the reservoir to the vessel accommodating the cleaning liquid by mounting a change-over valve at some midpoint of a hose connecting between the reservoir body and the increasing/decreasing device, or by providing a passage communicating with the vessel accommodating the cleaning liquid, in the side wall of the reservoir body. Further, it may be embodied by detaching the sliding projections and inserting a cleaning liquid pipe, instead of the detached sliding projections, or by providing a pipe for pouring a cleaning liquid into the sliding projection per se and so on. With the invention, since the vessel accommodating the cleaning liquid need not be transported, the process can be efficiently executed.
A thirty first aspect of the invention is an apparatus according to the first aspect, comprising a light measuring device for receiving light from all the vessels or plural liquid containing parts simultaneously or all together and measuring the strength of the light or processing the light as an image in order to measure a state of light emission.
With the invention, measuring light emission can be easily, efficiently and reliably executed, in comparison to the case where measurement of liquid emission is executed by moving a PMT device per liquid containing part or by mounting a PMT device for each liquid containing part.
A thirty second aspect of the invention is an apparatus according to the thirty first aspect, wherein the light measuring device comprises plural receiving components mounted at places corresponding to the liquid containing parts and having the same number as that of the liquid containing parts, and shading fences mounted between neighboring receiving components for preventing light from entering to other than the corresponding liquid containing part.
A thirty third aspect of the invention is a magnetic apparatus comprising, plural outer members capable of being mounted to and dismounted from a pipette device having a drawing/discharging device for drawing and discharging a liquid, and plural nozzles through the interior of which liquid passes due to the drawing and discharging, one or more vessels arranged with plural liquid containing parts, or column clusters arranged by plural columns, and capable of being brought into contact with or approaching to each outer surface of each nozzle, each liquid containing part or each column, while being mounted to the pipette device, the vessel or the column cluster, and a magnetic force device for applying a magnetic force to or removing the magnetic force from each nozzle, each liquid containing part or each column in a state with remaining stationary, by magnetizing and demagnetizing the outer members or by generating or extinguishing the magnetic field with coils which are mounted around each nozzle, each liquid containing part or each column while fitting to the pipette device, the vessel or the column cluster.
xe2x80x9cColumnxe2x80x9d means a liquid containing part comprising at least a mechanism capable of discharging a liquid such as a valve, and another mechanism for selectively drawing a liquid such as a valve.
With the invention, since the magnetic device can be mounted onto a pipette device, a vessel or a column cluster, and the process for target substances combined with the magnetic particles can be accumulated by utilizing the already existing pipette device, vessel or column cluster, and be utilized, the process can be executed at low cost.
A thirty fourth aspect of the invention is a magnetic apparatus according to the thirty third aspect, wherein the magnetic force device is the magnetic force device according to any one of the third to twenty first aspects applied to the nozzles, liquid containing parts or columns.
With the invention, the magnetic apparatus is applied to not only the pipette device arranged with plural nozzles but also to a vessel arranged with plural liquid containing parts or a column cluster arranged with plural columns. In the latter two cases, since the magnetic force device is applied to the liquid containing parts or columns, the diameter of each through section etc. is changed according to the liquid containing part or column.
A thirty fifth aspect of the invention, is an apparatus according to any one of the first to the thirty fourth aspects, wherein plural nozzles, plural through sections, plural reservoirs, plural sliding projections, plural hole parts, plural pushing pipes, plural liquid containing parts of the vessel, plural columns of the column cluster or plural receiving components are arranged in a plane-like state with a predetermined periodicity or a predetermined symmetry such as plural row-shaped, matrix-shaped, annular ring-shaped, polygonally, or radially.
xe2x80x9cMatrix-shapedxe2x80x9d means a state where plural elements are arranged at least in two directions (row direction and column direction) or in parallel, in a plane-like state. xe2x80x9cRowxe2x80x9d means the arrangement in the row direction, while xe2x80x9ccolumnxe2x80x9d means the arrangement in the column direction. The row direction and the column direction need not always cross at 90xc2x0. These directions may cross obliquely. Further, these plural elements may be arranged in a dense state while being alternately shifted by one between the neighboring rows or columns.
With the invention, integration can be facilitated. Since plural elements are arranged with a predetermined periodicity or symmetry, rotating movement and transposed movement (rows and columns are exchanged one with another) are possible by the pipette device according to the symmetry, and the control of movement and standardization are facilitated.
A thirty sixth aspect of the invention, is an apparatus comprising a reservoir body provided with plural pit-like reservoirs for storing drawn liquid arranged in a matrix, a sliding body with jutting plural sliding projections sliding through the reservoirs and capable of moving vertically to and from the reservoir body, plural nozzles attached to the lower parts of the reservoirs and capable of passing the liquid therethrough, a magnetic force device capable of magnetization and demagnetization having plural through sections in which is inserted each nozzle and having a wall part in contact with or near the outer side surface of the nozzle, with the nozzles inserted thereinto, wherein each wall part has two divided wall parts being apart from one another in such a manner that the divided wall parts have opposite polarities by magnetization, respectively.
A thirty seventh aspect of the invention is an apparatus according to any one of the first to thirty second aspects, the thirty fifth aspect, and the thirty sixth aspect, comprising a driving mechanism for driving the drawing/discharging device to draw and discharge, a magnetic controller for controlling the magnetic force of the magnetic force device, a transfer mechanism for transferring between vessels placed outside the pipette device, and the drawing/discharging device and the magnetic force device or between the drawing/discharging device and the nozzles and the magnetic force device, and an integrated process controller for controlling an integrated process of magnetic particles by controlling at least the driving mechanism, the magnetic controller, and the transferring mechanism according to instructions.
xe2x80x9cTransferringxe2x80x9d implies horizontal transferring, vertical transferring or rotational transferring. xe2x80x9cRotational transferringxe2x80x9d includes transferring by transposition.
With the invention, since the driving mechanism, the magnetic controller and the transferring mechanism can be handled by a single controller in a coordinated fashion, efficient, diverse and reliable control can be executed.
A thirty eighth aspect of the invention is an apparatus according to the thirty seventh aspect, wherein the controller controls an insulating device such as a ventilator, the pouring of cleaning liquid, a light measuring device, and data analysis, data disposition, or data output.
A thirty ninth aspect of the invention is an apparatus according to the thirty seventh aspect, wherein the controller controls either the strength, direction, or application time of the magnetic force, or magnetic patterns obtained from various combinations of strength, direction and time, according to the contents, conditions or objects of a target controlling step, the fluid, substances such as reagents, kinds, shape, quantity, combining state, or size of the magnetic particles, the pressure, the fluid velocity, the number of times of drawing/discharging, processes of transferring, agitation, cleaning, separation, removal extraction, reaction, clarification, concentration, dilution, recovery, isolation, or resuspension, external surroundings such as temperature, structure of the apparatus, materials or size of the apparatus, progress or schedule of magnetic control, degree of the residual magnetization, or instructions from the outside.
The degree of residual magnetization is obtained by measuring the magnetization with a coil of the magnetic force detecting device mounted near the apparatus or nozzle thereof. The measured results are fed back to the magnetic force device for use in control of the magnetic force device.
With the invention, according to the contents of the steps etc., precise, efficient, and reliable processes can be executed by controlling delicately to vary the strength, direction, or time for applying the magnetic field or the magnetic pattern obtained from a combination of the strength, direction, or time.
A fortieth aspect of the invention is an apparatus according to the thirty ninth aspect, wherein the controller controls in such a manner that the direction of the magnetization controlled by the magnetic controller is alternately reversed each time the magnetization is paused by demagnetization.
Therefore, since the direction of the magnetization in the wall parts etc. of the magnetic force device is alternately reversed, residual magnetization is offset, and magnetic noise due to the residual magnetization is reduced, even if the wall part is made of a para-magnet such as iron.
A forty first aspect of the invention is an apparatus according to the thirty ninth aspect, wherein the magnetic controller controls in such a manner that the direction of the magnetization is reversed with a strength or a driving time corresponding to that of the non-reversed magnetization, when changing a magnetized state to a demagnetized state.
Thus, generation of residual magnetization is prevented or the affect of the residual magnetization is reduced by generating magnetization that can offset the residual magnetization generated by the magnetization, according to the extent of the magnetization immediately before demagnetization.
A forty second aspect of the invention is a method comprising the steps of: drawing or discharging all together a fluid to or from a vessel comprising plural liquid containing parts by a drawing/discharging device mounted in the apparatus for an integrated process according to any one of the first to thirty second aspects, or the thirty fifth to forty first aspects, and applying the magnetic force to or removing the magnetic force from the nozzles in a state that remains stationary near the nozzles exterior, by generating or extinguishing the magnetic field with magnetization and demagnetization of the nozzle outer members mounted in contact with or near the periphery of the nozzles or a part of the nozzles, or by generation or extinguishing the magnetic field with a coil wound around the periphery of each nozzle.
A forty third aspect of the invention is a method according to the forty second aspect comprising further the steps of: mixing magnetic particles and the target substances by drawing and discharging all together with the apparatus for an integrated process, to make a suspension incorporating the magnetic particles combined with the target substances in plural liquid containing parts of the vessel, processing for separation by adhesion to the inner walls of the nozzles, elimination from the inner walls, transferring, resuspension, agitation, dissociation, extraction, reaction, clarification, concentration, dilution, recovery, isolation, or cleaning of the magnetic particles combined with the target substances by applying the magnetic force to, or removing a predetermined magnetic force from magnetic particles combined with the target substances within the nozzles, while drawing and discharging the liquid.
xe2x80x9cDissociationxe2x80x9d means removal of magnetic particles from the target substance, and xe2x80x9cextractionxe2x80x9d means the removal of the magnetic particles combined with the target substance, or only the target substance.
A forty forth aspect of the invention is a method according to the forty second aspect or the forty third aspect, further comprising a step for measuring all together light emission of the liquid accommodated in each liquid containing part and processed by the apparatus for an integrated process.
A forty fifth aspect of the invention is a method according to the forty third aspect, wherein the apparatus for an integrated process for magnetic particles whose plural nozzles are arranged in a matrix is used, and the processing for the transferring step comprises a transposed moving step for moving in such a manner that rows and columns of the nozzles of the apparatus for an integrated process or the liquid containing parts of the vessel, are exchanged, or a horizontal moving step for transferring in such a manner that rows and columns are not exchanged.
With the invention, combinations of a variety of substances can be efficiently and reliably generated all together by the transposed moving and the horizontal moving or a repetition of these movements.
A forty sixth aspect of the invention is a method of making any combined substances in carriers by arbitrarily combining with plural elements of substances, comprising the steps of: dispensing peach liquid incorporating each element of substances into one or more groups of containing parts arranged by plural containing parts in a matrix in which the containing parts accommodating said carriers are arranged in rows or columns having a predetermined number width in a way so as to be included in the matrix, according to the structure of the specified combined substances or the utilized kinds of containing parts, and mixing the dispensed elements of substances into the group of the containing parts accommodating the carriers, with the elements of substances arranged in rows or columns having a predetermined number width, in such a manner that row-like or column-like arrangements of the dispensed elements of substances are positioned against row-like or column-like arrangements of the elements of substances in a state of transposition or non-transposition.
xe2x80x9cElement of substancesxe2x80x9d implies for example, genetic substances such as DNA or RNA etc., or amino acids, xe2x80x9ccombined substancesxe2x80x9d implies for example, a variety of compounds such as DNA, RNA or peptides etc.
The invention may apply to not only the process using the magnetic particles as carriers, but also the process using the non-magnetic particles as polymer carriers. The vessel may have the liquid containing parts arranged in a matrix and may have a capturing function by mounting for example, a filter. Instead of vessels, columns arranged in a matrix and having a capturing function, may be used. The carriers may be solid carriers which are fixed to the surface of the liquid containing parts arranged in a matrix. Further, instead of having a capturing function in the vessel, a pipette device for drawing and discharging liquid, may have a capturing function by mounting a magnetic force device.
With the invention, combined substances of various structures can be integratedly generated by mixing the liquid incorporating elements of substances in such a manner that the row-like or column-like arrangements of liquids are transposed or non-transposed in a matrix. The invention may apply to combinatorial synthesis. The function for capturing the magnetic particles is embodied by the magnetic force device according to the thirty-third or the thirty-forth aspect.
A forty-seventh aspect of the invention, is a method according to the forty-sixth aspect for when the containing parts are liquid containing parts provided in a vessel and arranged in a matrix, comprising the steps of: disposing the carriers in the liquid containing parts of one of the one or more vessels, dispensing each liquid incorporating each element of substances into one or more vessels including vessels in which the carriers are disposed, in a state with rows or columns having a predetermined number width, according to the structure of the combined substances, and mixing each liquid incorporating each element of substances and disposed in a state with rows or columns having a predetermined number width in the other one or more vessels, with the dispensed liquid incorporating the elements of substances into the vessels in which the carriers are disposed, in such a manner that row-like or column-like arrangements of the dispensed elements of substances are positioned against row-like or column-like arrangements of the elements of substances in a state of transposition or non-transposition.
The invention may apply to the case where the magnetic particles are used as carriers (in the case including the case where a capturing carrier function is provided for the vessels, or a capturing carrier function is provided for the pipette device), the carriers are solid carriers fixed in the liquid containing parts, or the carriers are non-magnetic particles and the carrier capturing member is mounted in the vessels. The capture of the magnetic particles can be executed by the magnetic force device according to the thirty-third or the thirty-forth aspect.
A forty-eighth aspect of the invention is a method according to the forty-sixth aspect, for when the containing parts are plural columns arranged in a matrix and having a function for capturing carriers comprising the steps of, disposing the carriers to each column having a capturing function, dispensing each liquid incorporating each element of substances into the columns arranged in a matrix in a state with rows or columns having a predetermined number width, according to the structure of the specified combining substances, mixing the dispensed elements of substances into the group of the group of the columns accommodating the carriers, with the elements of substances arranged in rows or columns having a predetermined number width, in such a manner that row-like or column-like arrangements of the dispensed elements of substances are positioned against the row-like or column-like arrangements of the elements of substances in a state of transposition or non-transposition.
The invention may apply to the case where the carriers are magnetic particles or non-magnetic particles, or solid carriers. In the case where the carriers are magnetic particles, the capturing carrier function may be embodied by a magnetic field. In the case where the carriers are non-magnetic particles, the capturing carrier function may be embodied by a filter. In the case of solid carriers, the solid phase per se has the capturing function. The capturing magnetic particles function may be embodied by the magnetic force device according to the thirty-third aspect or the thirty-forth aspect.